The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.
Opioids are widely used in medicine as analgesics, for example in the treatment of patients with severe pain, chronic pain or to manage pain after surgery. Indeed, it is presently accepted that, in the palliation of more severe pain, no more effective therapeutic agents exist.
The term “opioid” is typically used to describe a drug that activates opioid receptors, which are found in the brain, the spinal chord and the gut. Three classes of opioids exist:    (a) naturally-occurring opium alkaloids. These include morphine and codeine;    (b) compounds that are similar in their chemical structure to the naturally occurring alkaloids. These so-called semi-synthetics are produced by chemical modification of the latter and include the likes of diamorphine (heroin), oxycodone and hydrocodone; and    (c) truly synthetic compounds such as fentanyl and methadone. Such compounds may be completely different in terms of their chemical structures to the naturally-occurring compounds.
Of the three major classes of opioid receptors (μ, κ and δ), opioids' analgesic and sedative properties mainly derives from agonism at the μ receptor.
Opioid analgesics are used to treat severe, chronic cancer pain, often in combination with non-steroid anti-inflammatory drugs (NSAIDs), as well as acute pain (e.g. during recovery from surgery and breakthrough pain). Further, their use is increasing in the management of chronic, non-malignant pain.
Optimal management of chronic pain requires around-the-clock coverage. In this respect, opioid-requiring cancer patients are usually given slow-release opioids (slow-release morphine, oxycodone or ketobemidone, or transdermal fentanyl or buprenorphine). Pharmaceutical formulations that are capable of providing a sustained release of active ingredients allow the patient to obtain this baseline analgesia with a minimal number of doses per day. This in turn improves patient compliance and minimizes interference with the individual's lifestyle and therefore quality of life.
Transdermal fentanyl drug delivery systems comprise patches (e.g. DURAGESIC®) that are applied to the skin to deliver that potent opioid analgesic, which is slowly absorbed through the skin into the systemic circulation. Pain may be relieved for up to 3 days from a single patch application. Transdermal buprenorphine patches (e.g. BUTRANS®) relieve pain for up to 7 days after a single patch administration.
In the design of sustained release formulations with extremely potent drugs, such as opioids, the risk for “dose dumping” has to be eliminated in view of the risk of severe and, on occasions, lethal side effects. Secondly, in some instances, patients may misuse their opioid medication, e.g. by willfully (and sometimes unintentionally) tampering with an extended release formulation in order to get more immediate absorption of opioid and a more rapid pain relieving effect. Thirdly, a perennial problem with potent opioid analgesics such as fentanyl is one of abuse by drug addicts. Addicts often apply innovative techniques in their abuse of pharmaceutical formulations, for example by way of one or more of the following processes:    (a) extracting a large quantity of active ingredient from that formulation using an appropriate eluent, such as an acid and/or alcohol, to form a solution, which is then injected intravenously. With most commercially-available pharmaceutical formulations, this can be done relatively easily, which renders them unsafe or “abusable”;    (b) heating (and then smoking);    (c) crushing of tablet (and then snorting); and/or    (d) in the case of a patch, making a tea (and then drinking).
Thus, there is a clear unmet clinical need for an effective pharmaceutical formulation that is capable of treating e.g. severe pain via a sustained release of active ingredients (such as opioid analgesics), whilst at the same time minimising the possibility of dose dumping, misuse by opioid treated patients and/or abuse by addicts.
One solution to these problems that has been suggested is the incorporation of the active substance into a polymer matrix (see e.g. US2003/0118641 and US2005/0163856), which allows for the slow release of the active substance. However, this solution is not adequate as the drug abuser could either liberate the active substance from the polymer matrix by co-mixing with a solvent (either prior to ingestion, or the solvent may be co-ingested with the polymer matrix/active substance) or by crushing the polymer matrix.
Ceramics are becoming increasingly useful to the medical world, in view of the fact they are durable and stable enough to withstand the corrosive effect of body fluids.
For example, surgeons use bioceramic materials for repair and replacement of human hips, knees, and other body parts. Ceramics also are being used to replace diseased heart valves. When used in the human body as implants or even as coatings to metal replacements, ceramic materials can stimulate bone growth, promote tissue formation and provide protection from the immune system. Dental applications include the use of ceramics for tooth replacement implants and braces.
Ceramics are also known to be of potential use as fillers or carriers in controlled-release pharmaceutical formulations. See, for example, EP 947 489 A, U.S. Pat. No. 5,318,779, WO 2008/118096, Lasserre and Bajpai, Critical Reviews in Therapeutic Drug Carrier Systems, 15, 1 (1998), Byrne and Deasy, Journal of Microencapsulation, 22, 423 (2005) and Levis and Deasy, Int. J. Pharm., 253, 145 (2003).
In particular, Rimoli et al, J. Biomed. Mater. Res., 87A, 156 (2008), US patent application 2006/0165787 and international patent applications WO 2006/096544, WO 2006/017336 and WO 2008/142572 all disclose various ceramic substances for controlled release of active ingredients, with the latter two documents being directed in whole or in part to opioid analgesics, with the abuse-resistance being imparted by the ceramic structures' mechanical strength.
Methods employed in these documents typically involve the incorporation of active ingredients into pre-formed porous ceramic materials comprising e.g. porous halloysite, kaolin, titanium oxide, zirconium oxide, scandium oxide, cerium oxide and yttrium oxide. In this respect, loading of active ingredient typically comprises soaking, extrusion-spheronization and/or cryopelletization. It is known to be difficult to infuse drug into a pre-formed porous ceramic structure. Indeed, in the case of opioids, it is considered that such active ingredient-incorporation methodology will not enable the loading of sufficient active ingredient to provide appropriate doses for effective therapeutic pain management, over a prolonged time, given that infusion of active ingredient into preformed pores is a difficult thing to do.
In WO 2008/142572, drugs are incorporated during the formation of a ceramic carrier using chemically bonded ceramics, such as calcium aluminate or calcium silicate. Although this leads to a higher amount of drug incorporation than is typically the case for preformed ceramic materials, the mechanical strength and the chemical stability of the ceramic structures described in WO 2008/142572 is, relatively speaking, limited, especially in acidic conditions. See also Forsgren et al, J. Pharm. Sci., 99, 219 (2010) and Jämstorp et al, J. Control. Release (2010) in press.
A composite material having a beneficial agent associated with at least a portion of a high surface area component so as to increase the bioavailability and/or activity of the beneficial agent is disclosed in WO 02/13787. The high surface area component may be formed from a material having a hardness that is greater than the hardness of the beneficial agent, and may be formed from metal oxides, metal nitrides, metal carbides, metal phosphates, carbonaceous materials, ceramic materials and mixtures thereof. The beneficial agent may be associated with the high surface area component by means of spraying, brushing, rolling, dip coating, powder coating, misting and/or chemical vapour deposition.
Various methods of enhancing drug delivery by transdermal administration are described by Banga in Expert Opin. Drug Deliv., 6, 343 (2009), including direct coating onto microneedles and administration via hollow microneedles. See also international patent application WO 03/090729 and WO 2009/113856, U.S. Pat. No. 6,334,856 and US patent application No. US 2009/0200262.
An interface for a transdermal drug administration device is disclosed in US 2007/0123837. The interface may be provided in the form of a flat plate including two-dimensionally arranged projections, capable of piercing the skin, and a plurality of openings, capable of delivering a drug, respectively arranged in correspondence with the projections. The projections may be conical or pyramidal in shape and the flat plate and projections may be formed from a metal, an alloy or a ceramic. In use, in a transdermal drug administration device for example, a drug in liquid form may be held in a drug-containing layer above the flat plate. When the flat plate is pressed against the skin, the plurality of projections pierce the skin and the drug is transferred from the drug-containing layer, via the plurality of openings provided in correspondence with the projections, through the holes formed in the skin.
A device for delivering bioactive agents through the skin is also disclosed in WO 03/092785. The device includes a plurality of skin-piercing members and a porous calcium phosphate coating adapted as a carrier and provided on at least part of the skin-piercing members. The coating includes at least one bioactive agent and the skin-piercing members may be formed from metals, ceramics, plastics, semiconductors or composite materials.
Each of these documents refers to the possibility of loading and/or combining an active ingredient with a pre-formed delivery device or other carrier, either by means of a separate drug-containing layer provided in combination with the device or a coating applied to the device.